Worrying About Killer Flu

Asia is brewing a deadly virus, but only with the right ingredients can it morph into an epidemic

Hanoi’s crowded poultry markets create opportunities for pathogens to spread easily and become deadly. A virulent strain of avian flu, H5N1, first turned up in China in 1997 and reemerged in Southeast Asian nations in 2004. To keep the virus from spreading, officials ordered millions of chickens killed.

Courtesy of Timothy M. Uyeki

In the markets of Guangdong province, which borders on the South China Sea, thousands of chickens, ducks, quail, and geese squawk endlessly, crammed into cages next to or stacked on top of wilder creatures—civet cats, raccoon dogs, snakes, and turtles. Customers can walk into a stall, select dinner from the noisy multitude, then sit down to await the animal’s slaughter.

A crowded stall in Guangdong is where the virus that causes severe acute respiratory syndrome (SARS) jumped from an animal, probably a civet cat, into a human in 2003. From there it went on to kill at least 800 people, make 8,000 others extremely ill, and drag down the economies of several Asian countries. The markets of Guangdong are also the source of H5N1, a strain of killer avian flu that first jumped from animals to people in 1997 and then reemerged last year. H5N1 is getting far more attention than SARS from scientists who study the ecology of viruses because, of the 44 people who are known to have gotten H5N1 in 2004, 32 died. Such a high ratio of death to infection has researchers scrambling to track the virus and prevent its spread. Their worst-case scenario is that a highly virulent bird flu virus could mingle with a human flu virus to spark a pandemic like the Spanish flu of 1918, which killed at least 20 million people.

“Prior to 2004, most of us thought that a 1918 pandemic would never occur again, but now we are not so sure,” says Tim Uyeki, an epidemiologist at the Centers for Disease Control and Prevention in Atlanta. “Widespread circulation of H5N1 viruses among poultry in Asian countries is now considered a ticking time bomb for humans. The key to reducing the public-health risk of a pandemic is to control H5N1 among poultry.”

Of the 15 distinct types of flu strains known to occur in birds, H5N1 is “right at the top of the list for most-wanted strains,” says Richard Webby, a virologist at St. Jude Children’s Research Hospital in Memphis. And yet, as deadly to humans as it is, H5N1 is also very difficult to contract. It is “particularly poor at infecting humans and worse still at transmitting from human to human,” says Webby. What scientists still have not figured out about this strain is how much it must mutate before it can infect people easily. “Is it 3 amino acid changes away, or 300?” asks Webby.

Some flu experts fear that if a deadly virus like H5N1 can mutate enough to spread easily among people, no one will be prepared to deal with it. There is only a preliminary form of a vaccine against H5N1 flu strains, and even if there were a developed vaccine, the virus might spread faster than public-health officials could get people inoculated. Knowledge—understanding how flu viruses work so they can be stopped early in their journey—is likely to be the best protection we have against another epidemic.

Viruses like avian flu or the animal coronavirus that mutated into SARS must be relatively benign in their original hosts to spread from one animal in the wild to the next. Thus avian influenza in migratory birds like wild ducks has evolved to be mild, says Paul Ewald, who studies the evolution of infectious diseases at the University of Louisville in Kentucky. When flu strains become too lethal among migratory birds, the birds die out before they can spread the infection to a new area.

A mild virus becomes lethal when wild animals enter markets like Guangdong, which serve as factories for disease. The animals’ close confinement allows the virus to exploit more of its host’s tissues because it does not need to keep the host healthy to spread the infection. The next victim is right at hand, an inch or so away. Among birds in close confinement, a virus rapidly evolves the ability to transmit, not only through feces but also via the respiratory system. A single infected bird can breathe a virus into the face of many birds, with swift and disastrous results. The H5N1 strain causes tiny blood vessels throughout the body of a chicken, for example, to collapse. In some cases, the bird begins to bleed through its orifices; its comb appears to melt. Soon the entire cage is filled with bleeding, dying chickens.

The strains of H5N1 that have managed to jump species and infect people are those that are most deadly to chickens, says David Swayne, a veterinarian at the U.S. Department of Agriculture. Chicken handlers and others exposed to sick birds or their droppings are most at risk. In the case of the avian flu epidemic that broke out in December 2003 and continued into the fall of 2004, 43 of the 44 people known to have contracted the disease appeared to have done so directly from animals. A mother who held her dying child close is the only person who seems to have contracted the disease from another person.

Webby says nobody knows how many mutations it would take to permit H5N1 to pass among humans as easily as other flus do. What researchers do know is that influenza is an RNA virus, which mutates easily and rapidly. It has only eight genes, and two of the genes produce antigens, a type of protein that stands out on the surface of the virus particle. The two surface antigens are called hemagglutinin and neuraminidase, the H and N in H5N1. The human immune system is adept at recognizing antigens it has met before: Antibodies snap onto the projecting viral proteins and prevent the organism from infecting other cells. Flu viruses can evade immune-system scouts by constantly shifting surface antigens. Small changes in the H and N antigens are referred to as antigenic drift. When drift occurs each year, a new influenza vaccine must be made.

Although each new vaccine is designed to protect against the previous year’s flu, many people get partial immunity to new strains because the surface proteins often don’t look all that different to the immune system. What keeps epidemiologists up at night is antigenic shift, a radical change in surface proteins that presents the immune system with a completely different face. When this happens, no one has any immunity.

Extreme shifts in surface proteins explain why existing vaccines offer no protection against the new avian flu. More important, altered surface antigens explain how the three major flu pandemics of the last century—1918, 1957, and 1968—spread through the world like firestorms. The 1957 pandemic killed about 70,000 people in the United States. In the winter of 1968–1969, about 34,000 people in the United States died. Mystery still surrounds the greatest pandemic, in 1918, which probably killed more people than any disease outbreak since the Black Death of 1347–1351.

Molecular pathologist Jeffery Taubenberger of the Armed Forces Institute of Pathology, who has analyzed the 1918 flu strain, H1N1, says it shared characteristics with modern avian flu strains. But unlike the pandemic strains of 1957 and 1968, which appear to have resulted from the direct mixing of avian and human flu strains, the 1918 strain doesn’t seem to have jumped directly from birds to humans. “Perhaps,” he says, “it spent time in other animals” before infecting people.

Uyeki worries about the opportunities that could permit H5N1 to spread easily among humans. If someone became infected at the same time with both H5N1 and a human flu, he says, the two variants could mingle to “create a new strain with efficient and sustained person-to-person spread. This could cause a pandemic.” Another scenario envisioned by scientists has avian and mammalian flu strains mixing in some other species, perhaps pigs. Webby says it’s unlikely: “You’d have to have a pig catching influenza both from a human and from a chicken at the same time. Avian viruses do not do well in most mammalian species. Certainly the virus has to change before it can adapt to humans. It has been in millions of birds, but there have only been 44 human cases. At this moment there is no way to assess the risk. So we need to know how well an H5N1 and a human flu virus can get on with each other.”

There is at least one known barrier to avian influenza taking hold in humans. A study published last March shows that avian flu strains can infect cells lining the human respiratory system, but they seem to have difficulty replicating. Avian flus prefer to bind to cells that have hairlike appendages called cilia. Human influenza viruses prefer to infect nonciliated cells. To spread effectively from human to human, avian flu strains would have to adapt to nonciliated cells.

The evolution of the SARS virus—like flu, an RNA virus—is a vivid example of how a pathogen incubated in the markets of Guangdong managed to jump species and adapt to humans. Molecular analysis shows that SARS is closely related to coronaviruses found in civet cats in the animal markets of Guangdong, though scientists are still not certain that civets were the original reservoir. Research published in early 2004 shows that the viruses from all known human cases of the 2003 outbreak seem to descend from the same lineage. Somewhere along the way, certain molecular changes, including a deletion of 29 base pairs from the original virus, allowed SARS to infect and replicate in human cells. At first the virus infected only 3 percent of people who had person-to-person contact with a SARS patient. By the end of the outbreak seven months later, the infection rate from such contact had risen to 70 percent. One of the crucial adaptations involved changes in a gene that encodes a viral protein used to enter cells. At the beginning of the outbreak, many variants of the gene existed. Within just 15 weeks, only one version dominated—the type best suited for infecting humans.

SARS is frightening, says molecular virologist Earl Brown at the University of Ottawa, because it infects deep tissues. It isn’t confined, like most human coronaviruses, to the upper respiratory tract. SARS not only ravaged people’s lungs, it also invaded the digestive system and was produced in large quantities in human feces. That preserved the virus longer in the environment. One SARS patient with diarrhea managed to infect 321 other people in an apartment complex because faulty plumbing aerosolized his feces, allowing them to drift on wind currents into other apartments.

SARS developed into a stable organism adapted to growing and transmitting among human beings in a very short time, says Brown. Yet it never evolved into a pathogen that moved as efficiently as human flu. Brown notes that SARS spread late in the course of infection, when patients were already immobilized. The viral load in a body increased throughout the course of the illness, making people at once sicker and more contagious. Hospital staff, using supportive care procedures like putting breathing tubes down throats, often contracted SARS themselves, despite double gowns, gloves, and masks. Carlo Urbani, the Italian physician who informed the world that SARS had reached Vietnam, died of the infection.

Despite intensive study, no one understands why some patients gave SARS to other people and others did not. While many victims, including eight people who traveled to the United States, did not spread the disease to anyone else, some superspreaders infected many. One event took place at the Hong Kong Metropole Hotel in February 2003. A physician from Guangdong who had come to Hong Kong for a wedding fell violently ill. He apparently coughed, spat, or vomited on the floor of the hallway near his room. At least 16 people staying on or visiting the same corridor became infected. They returned to their homes and seeded the infection in Singapore, Canada, and Vietnam.

After more than seven months, the SARS outbreak ended because public-health officials, doctors, and nurses managed to break the chain of transmission—at considerable risk to themselves and despite superspreader anomalies, such as an elderly woman who managed to infect 16 other people as she waited for treatment in an emergency room near Toronto.

Donald Low, an infectious-diseases physician from Mount Sinai Hospital in Toronto, argues that there have been low-level introductions of a SARS-like virus in Guangdong for years. About 40 percent of workers in the animal markets there have antibodies to the disease. Four cases of a SARS-like coronavirus that emerged in Guangdong last year were different, both clinically and molecularly, from human SARS, which suggests he is correct. Biologist Ewald says, “Given enough time, I think the chance mutational events that made the virus transmissible from human to human could happen again—it might be in 10 or 100 years.”

Despite causing social disruption and fatalities, SARS never moved as quickly and widely as influenza. Most cases of SARS gave rise to one new case, whereas each case of human flu can easily give rise to 10 new cases. “Imagine if that had been virulent flu,” says Allison McGeer, a physician at Mount Sinai Hospital who was at the epicenter of the Toronto SARS outbreak in 2003. “We would not have the capacity to handle it.”

Although any new pandemic would be costly and dangerous, there are good reasons to think that avian flu would be unlikely to morph into a strain that is both virulent and highly transmissible among humans. As Ewald has pointed out, the 1918 flu may have developed its unique virulence, and its unique focus on young adults, precisely because of the terrible conditions in wartime Europe. The disease first appeared as a relatively mild outbreak in the United States in the spring of 1918. A far deadlier form incubated among soldiers on the Western Front. It stalked the trenches, the hospitals stacked with wounded, sick, and dying soldiers, the trucks that carted sick and wounded from one crowded hospital to another, the trains on which the immobilized sick lay face-to-face with the helpless wounded, and the boats that returned ill soldiers to the United States.

Only comparable conditions, Ewald says, would allow the development of a highly virulent and transmissible human flu. As the conditions that created the 1918 flu abated, so did the virulence of the disease and its specificity for healthy people in the prime of life. But it did not disappear. For decades after 1918, H1N1 wandered around the planet, a commonplace flu, no more virulent than any ordinary strain, a killer of the very old and the very young. It spread the way human flu strains always do—coughs and sneezes. Precisely because people have to be healthy enough to walk around and cough into other people’s faces, ordinary human flu strains must be relatively mild to spread. Lethal flu requires the sort of conditions found in the animal markets of Guangdong or the trenches of World War I.

The first introduction of disease from chickens or civets does not produce a pandemic. The disease must spread from desperately ill people who are so sick they cannot walk around. Only when people are packed together, when the immobilized sick are in close contact with the well, does the threat of a human disease factory loom.

“It’s not impossible to develop highly virulent and successfully transmitting pathogens like the 1918 flu,” says Brown. Crowded hospital emergency rooms, where very ill people would be brought, could serve as transitory disease factories, as they did with SARS. Advanced care in hospitals, involving respirators and intubations, may have the same effect. Other environments are even more dangerous for breeding deadly pandemics. “Don’t have shantytowns and refugee camps all over the world,” says Brown. “Those are the environments where people can’t clean themselves and are forced to live cheek by jowl.”

Avian flu and SARS on the move

Six years after the H5N1 avian flu first appeared in China, it reemerged in December 2003 in Korea and Japan and spread like wildfire. By February 2004, most Southeast Asian countries had reported outbreaks. In the meantime, millions of chickens and ducks were slaughtered to try to contain the virus.

Unlike SARS, H5N1 has yet to spread among humans. But it has proven deadly. By October 2004, the World Health Organization reported 43 cases of people contracting H5N1 by handling infected poultry, resulting in 31 deaths. Only one case of human-to-human transmission has been documented.

The 2003 SARS epidemic not only spread quickly but also far and wide. After the virus surfaced in China, travelers carried it around the globe. Ultimately, 8,000 people were infected, and at least 800 died.